KR101870979B1 - Formulations for the treatment of disorders of the upper respiratory tract - Google Patents

Abstract

The present invention relates to formulations containing extracts of bacillium mirtillus or other anthocyanoside-enriched species, fenicago granatum, echinacea, and optionally krameria triandra. Such formulations are useful for the treatment of oral and adnexal, throat and respiratory disorders, and for the treatment of influenza.

Description

[0001] The present invention relates to a formulation for the treatment of disorders of the upper respiratory tract,

The present invention relates to a process for the preparation of < RTI ID = myrtillus ) or other anthocyanoside-rich species, Punica granatum , Echinacea , and optionally Krameria triandra ). < / RTI > Such agents are useful for the treatment and prevention of oral and adnexal, throat and respiratory disorders, and for the treatment of influenza.

In particular, the combination according to the invention, contained in a suitable carrier, is particularly useful for bacterial and viral disorders in infancy.

Along with the formation of plaques, reddening, inflammation, and bacterial and / or fungal infections of the throat are symptoms associated with generalized influenza, cold, and similar disorders. Common colds and influenza, affecting children and adults on average three times a year, are mainly associated with viral infections, 40% of which are caused by rhinoviruses, 10% by coronaviruses, and Low rates are caused by adenovirus and parainfluenza virus.

Influenza affects millions of people around the world, with frequent and serious complications that weaken the mind and body of the patient from the public health point of view every year and cause serious death, As a result, preventive and curative treatment of influenza is an important goal.

Influenza is particularly dangerous to the elderly because of its complications or respiratory disorders typically present in elderly patients. The same problem can be caused by infants because influenza in infants leaves aftermath of repeated colds and recurrences. Over the years, vaccination has been considered the most effective way to deal with viral diseases; However, its efficacy is limited by the peculiar antigenic mutability resulting from the emergence of new viral strains that can overcome immunity that resisted earlier strains.

Although there is no specific treatment for these disorders, antihistamines, decongestants and anti-inflammatory agents are considered useful because alleviation of edema alleviates pain and shortens the duration of the disorder that is the source of inflammation. These obstacles are often accompanied by complications from the onset of secondary bacterial infections, as the exit of the sinus is often blocked by mucosal congestion, which can easily multiply, causing fever and local pain. In this case, antibiotic or bacteriostatic treatment is required in addition to symptomatic treatment. However, especially in infants, antibiotics weaken the defense of the body, causing recurrence.

Neuraminidase inhibitors introduced over the last decade also cause low efficacy, and often lead to the induction of toxicity and viral resistance. Because these substances have different effects on strains A and B, substances that attack both species are essential if the type of infection is not known a priori.

However, not all drugs available in the market today can be used for children and pregnant women. This means that antiviral agents that are harmless to both adult patients (including pregnant women) and children and that do not cause the development of resistant viruses are essential.

Now, Vaccinium myrtillus or other anthocyanoside-rich species, Punica granatum extract, Echinacea extract, and optionally Krameria extract triandra extract of the present invention is useful for the treatment and prevention of a number of strains of influenza A and B and a variety of strains of adenovirus, paramyxovirus, herpes catarrhalis virus, cytomegalovirus and respiratory syncytial virus has been shown to be effective in the treatment of oral and adnexal, throat and respiratory disorders, and in the prevention and treatment of influenza, as a result of its remarkable antiviral activity against respiratory syncytial virus.

The present invention therefore relates to:

a) an extract of a species rich in bacillium mirtillus or other anthocyanosides;

b) Punikagranatum extract;

c) Echinacea extract;

And optionally

d) a novel formulation comprising Krameria triandra extract.

According to the present invention, the term " Vaccinium myrtillus or other species "includes plants containing anthocyanosides. The anthocyanosides present in these plants are mainly cyanidin and delphinidin glucosides which have been described for their activity in relation to capillary protection, inflammation, angiogenesis and immune control.

The anti-inflammatory effect performed by anthocyanoside is associated with NFkB inhibition and its anti-angiogenic potential; Since the angiogenic process is essential for inflammation and angiogenesis depends on vascular endothelial growth factor (VEGF), these parameters are evaluated and activity is known at the nanomolar level. The molecule also inhibits 5- and 12-lipoxygenase at nanomolar concentrations. Nuclear factor NF-kB, which is involved in both inflammation and immune responses to infection, is significantly inhibited by anthocyanins and tannins and their metabolites, and these factors are also inhibited at nano-mol concentrations.

According to the present invention, the Ponikagranatum extract is an extract obtained from a fruit having a polyphenol content of 90%. The extracts have demonstrated antiviral and weak anti-bacterial properties that increase body defense by further synthesis of interferon gamma.

The preparation of this extract is carried out by extracting from the fruit and / or the upper part of the plant with a C1 to C3 alcohol diluted with water, preferably a 50% v / v mixture of ethanol / water; Then concentrating the water / ethanol extract until the organic solvent is completely removed, treating the suspension with polyvinylpyrrolidone in an amount corresponding to 0.2% of the biomass weight, filtering to remove undesired polymeric tannins, The absorption of the transparent solution into the polystyrene resin, and the washing of the resin until the soluble material is completely removed. The active ingredient constituting the extract used in the present invention is recovered by washing the resin with 90% ethanol. Concentration of the ethanol eluate to a small volume and drying of the residue under vacuum at a temperature not exceeding 50 DEG C provides a polyphenol-enriched extract.

According to the present invention, the extract of Echinacea is preferably selected from the group consisting of Echinacea angustifolia ) and / or purpurea . < / RTI >

Antimicrobial activity and antiviral activity of Echinacea extract, especially Streptococcus piegensis pyogenes , staphylococcus aureus, aureus, penicillin-resistant), Haemophilus influenzae (Haemophilus influenzae) and Legionella pneumophila (Legionella Antimicrobial activity and antiviral activity against pneumophila species have been described. This activity has been associated with both polyphenol parts and isobutylamide-rich lipophilic parts of polyunsaturated acids (Phytomedicine, 17, 563, 2010). Isobutylamide is a potent ligand of the cannabinoids and vanilloid TRPV1 receptors, and as a result acts on pain, inflammation and immune responses. Cannabinoid agonist compound also has, associated with enhancement of the immune response, as demonstrated recently for cannabis (Cannabis) derivative.

According to the present invention, the Krameria triandra extract is a water / alcohol extract obtained from the root and the upper part of Krameria triandra, which has been purified according to the procedure described above for the production of the fungus licorice extract. The Krameria triandra extract thus obtained has a benzofuran content of 14% and an ella tannin content of 70% and a protocatechium tannin content. Krameria extract is known for its antibacterial and antifungal action at microgram concentrations per mL.

It has surprisingly been found that the preparations according to the present invention have an activity significantly exceeding the antimicrobial activity and antiviral activity of the various extracts when administered separately, and it has been found from the therapeutic or prophylactic point of view that the antimicrobial activity An unpredictable in vivo synergistic mechanism that increases activity and antiviral activity ( in vivo synergic mechanism.

The preparations according to the invention have been shown to be largely active against most common viral species, in particular influenza virus, and to prevent the formation of bacterial plaques with fever accompanied by cold and influenza normally. These agents are also generally effective for purulent otitis media and oral infection.

According to a preferred aspect, the preparations according to the invention comprise the active ingredient in the following weight fractions per unit dose:

a) an extract of a species rich in bacilliium mirtillus or other anthocyanosides: 20 to 80 mg;

b) Punikagranatum extract: 20 to 40 mg;

c) Echinacea extract: 20 to 100 mg;

And optionally

d) Krameria triandra extract: 10 to 30 mg.

According to a particularly preferred aspect, the composition according to the invention will comprise the active ingredient in the following weight range per unit dose:

a) an extract of a species rich in bacitanium mirtillus or other anthocyanosides: 40 to 60 mg;

b) Punikagranatum extract: 25 to 35 mg;

c) Echinacea extract: 40 to 60 mg;

And optionally

d) Krameria triandra extract: 15-20 mg.

The pharmaceutical preparations used are usually formulated as tablets which slowly dissolve in the mouth or as chewing gum which slowly releases the active ingredient. These agents are used not only for prophylactic treatment but also for healing and for oral hygiene.

Therefore, the preparation will be formulated with suitable excipients according to well-known conventional methods, as described in "Remington's Pharmaceutical Handbook ", Mack Publishing Co., N. Y., USA.

The following examples illustrate the present invention in detail.

Example  I - including 1000 mg Chewing jung  ( chewable tablet )

Punicagranatum extract 30.0 mg

Baccinium myrtillus extract (40% anthocyanoside) 60.0 mg

Echinacea extract 50.0 mg

Mannitol 429.5 mg

Fructose 300.0 mg

10.0 mg of anhydrous citric acid

Carboxymethylcellulose sodium salt 40.0 mg

Glyceryl behenate 20.0 mg

Sodium saccharin 0.5 mg

Soft fruit flavoring 20.0 mg

Example II  - 1000 including mg  Chewing jung

Ponikagranatum extract 40.0 mg

Bakuminium mirtillus extract (40% anthocyanoside) 80.0 mg

Krameria triandra extract 35.0 mg

Echinacea extract 50.0 mg

Saccharose 472.0 mg

Mannitol 230.0 mg

10.0 mg of anhydrous citric acid

Carboxymethylcellulose sodium salt 40.0 mg

Glyceryl behenate 20.0 mg

Sodium saccharin 0.5 mg

Ammonium glycyrrhizinate 3.0 mg

Zhangyu spices 20.0 mg

Example III  Granules for instant suspension comprising

Ponikagranatum extract 40.0 mg

Baccinium myrtillus extract (40% anthocyanoside) 60.0 mg

Krameria triandra extract 20.0 mg

Echinacea extract 50.0 mg

Mannitol 900.0 mg

Guar gum 100.0 mg

Sodium cyclamate 21.0 mg

30.0 mg of anhydrous citric acid

Ammonium glycyrrhizinate 10.0 mg

Acesulfame K 3.0 mg

Hydroxypropylcellulose 1.0 mg

Example IV  Granules for instant suspension comprising

Ponikagranatum extract 40.0 mg

Baccinium myrtillus extract (40% anthocyanoside) 60.0 mg

Echinacea extract 50.0 mg

Mannitol 920.0 mg

Guar gum 100.0 mg

Sodium cyclamate 21.0 mg

30.0 mg of anhydrous citric acid

Ammonium glycyrrhizinate 10.0 mg

Acesulfame K 3.0 mg

Hydroxypropylcellulose 1.0 mg

Example  Ⅴ - Biological activity

The composition according to the present invention was tested on six groups of 10 male and female patients suffering from bacterial infection of the oral cavity.

The patient was administered a combination (Example II) or a tablet containing a single component three times a day for three days. One hour before and one hour after the last administration, the redness of the pharyngeal and tonsil is measured on a 4-point scale (no = 0, slight = 1, moderate = 2, severe = 3 ).

The results are shown in Table 1.

Inflammation of pharynx and tonsils Base value After administration The tablets described in Example II, containing only 30 mg of Ponikagranatum extract 2.2 1.9 The tablets described in Example II, containing only 60 mg of Baccinium myrtillus extract (40% anthocyanoside) 1.9 1.5 The tablets described in Example II, containing only 50 mg of Echinacea extract 1.8 1.7 The tablets described in Example II, containing only 20 mg of Krameria triandra extract 2.1 2.0 The tablets described in Example II 2.3 0.4 Placebo 1.8 1.8

At the same time, the patients were gargled with 10 mL of sterile distilled water for 20 seconds and samples were collected.

The sample was appropriately diluted with a Ringer's solution containing 0.2% dithiothreitol and 0.5 mL of each dilution was plated on four agar plates (Columbia) supplemented with 5% sheep blood; This plate culture was incubated in a CO ₂ atmosphere for anaerobic culture for 72 hours. After incubation, the number of colonies was counted.

The results are shown in Table 2.

Water Fertilization ( gargling ) (X 10 < / RTI > ⁵ ) Base value After administration The tablets described in Example II, containing only 30 mg of Ponikagranatum extract
37.0
33.0 The tablets described in Example II, containing only 60 mg of Baccinium myrtillus extract (40% anthocyanoside)
38.4
30.4 The tablets described in Example II, containing only 50 mg of Echinacea extract
29.9
27.3 The tablets described in Example II, containing only 20 mg of Krameria triandra extract
31.4
26.3 The tablets described in Example II 36.2 6.7 Placebo 31.1 30.9

Claims (7)

a) an extract of Vaccinium myrtillus ;
b) an extract of Punica granatum ;
c) an extract of Echinacea ; And
d) an extract of Krameria triandra ,
An agent for the treatment and prevention of oral bacterial infection or inflammation. The preparation according to claim 1, wherein the extract of Ponica granatum is an extract obtained from fruit having a polyphenol content of 90%. The method according to claim 1, wherein the extract of Echinacea is an extract of roots and ground parts of Echinacea angustifolia , purpurea , or a combination thereof,
Wherein the extract is extracted with a mixture of alcohol and water. [Claim 3] The composition according to claim 1, wherein the extract of Krameria triandra has a benzofuran content of 14% and a content of ellagitannin and protocatechuic tannin of 70% And,
Wherein the extract is extracted with a mixture of alcohol and water. The preparation according to any one of claims 1 to 4, comprising an active ingredient in the following weight range per unit dose:
a) an extract of Baccinium myrtillus: 20 to 80 mg;
b) Extract of ponikagranatum: 20 to 40 mg;
c) Echinacea extract: 20 to 100 mg; And
d) Extract of Krameria triandra: 10 to 30 mg. The formulation according to claim 5, comprising an active ingredient in the following weight range per unit dose:
a) extract of bacitanium mirtillus: 40 to 60 mg;
b) an extract of Punikagranatum: 25 to 35 mg;
c) Echinacea extract: 40 to 60 mg; And
d) Extract of Krameria triandra: 15-20 mg. delete